Search

Abstract Background Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC. Methods KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1. Results One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2–14.3) and 10.3 months (2.7–13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2–44.1] and sunitinib/pazopanib (29.2% [18.6–41.8]). Grade 3–5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects. Conclusions ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab. Clinical trial registration ClinicalTrials.gov; NCT03260894 .

Background Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures.Methods Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method.Results At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs.Conclusions Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN.Trial registration number NCT02231749.

Background: Immuno-oncology (IO) agents and tyrosine kinase inhibitors (TKIs) have revolutionized the treatment paradigm for metastatic renal cell carcinoma (mRCC). Data on real-world usage and outcomes are limited. Objective: To examine real-world treatment patterns and clinical outcomes for mRCC. Design, setting, and participants: This retrospective cohort study included 1538 patients with mRCC who received first-line treatment with pembrolizumab + axitinib (P + A; n = 279, 18%), ipilimumab + nivolumab (I + N; n = 618, 40%), or TKI monotherapy (TKIm; cabozantinib, sunitinib, pazopanib, or axitinib; n = 641, 42%) between January 1, 2018 and September 30, 2020 in US Oncology Network/non-network practices. Outcome measurements and statistical analysis: The relationship with outcomes, time on treatment (ToT), time to next treatment (TTNT), and overall survival (OS) was analyzed using multivariable Cox proportional-hazards models. Results and limitations: The median age of the cohort was 67 yr (interquartile range 59.5–74.4), 70% were male, 79% had clear cell RCC, and 87% had an intermediate or poor International mRCC Database Consortium risk score. The median ToT was 13.6 for P + A versus 5.8 for I + N versus 3.4 mo for TKIm (p

Abstract Background Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. Methods Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. Results Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. Conclusions These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment. Trial registration The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.

Based on the S-TRAC results, sunitinib is approved as adjuvant treatment for adult patients at high risk of recurrent RCC following nephrectomy. Here, the authors report the results of an integrated multi-omics tumor analysis of 171 patients from the trial and identify specific molecular subtypes as well as potential new targets.

Background Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and limited therapeutic options. First-line nivolumab plus ipilimumab (NIVO+IPI) provided efficacy benefits over sunitinib (SUN) in patients with intermediate/poor-risk sRCC at 42 months minimum follow-up in the phase 3 CheckMate 214 trial. In this exploratory post hoc analysis, we report clinical efficacy of NIVO+IPI in sRCC after a minimum follow-up of 5 years.Methods In CheckMate 214, patients with clear cell advanced RCC were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks (four doses), then NIVO 3 mg/kg every 2 weeks versus SUN 50 mg once daily (4 weeks; 6-week cycles). Randomized patients with sRCC were identified via independent central pathology review of archival tumor tissue or histological classification per local pathology report. Overall survival (OS), as well as progression-free survival (PFS) and objective response rate (ORR) per independent radiology review using Response Evaluation Criteria in Solid Tumors V.1.1, were evaluated in all International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk sRCC patients and by baseline tumor PD-L1 expression level (≥1% vs

Background: The lenvatinib (LEN) plus everolimus (EVE) combination demonstrated improved progression-free survival over everolimus alone in a phase 2 trial (Study-205). Objective: To compare quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) between LEN + EVE and EVE alone among patients with advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy. Design, setting, and participants: This was a post hoc analysis of Study-205. Outcome measurements and statistical analysis: Survival time was partitioned into three mutually exclusive health states: time with grade 3/4 toxicity (TOX); time before disease progression and without grade 3/4 toxicity (TWiST); and time after disease progression (REL). The mean time in each state was weighted by utility measures and summed to calculate Q-TWiST. Nonparametric bootstrapping generated 95% confidence intervals (CIs). In the base case, utility for TWiST, TOX, and REL was assigned as 1.0, 0.5, and 0.5, respectively. Sensitivity analyses applied alternative utility values for REL, TOX, and TWiST. A relative gain in Q-TWiST of ≥10% and ≥15% has been established as clinically important and clearly clinically important, respectively. Results and limitations: Patients receiving LEN + EVE (n = 51) had a significant mean Q-TWiST gain of 3.7 mo (14.7 vs 11.0 mo; 95% CI for difference 1.3–6.3), with a relative gain of 24% compared to EVE alone. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 to 0.9) with utility set to 0.5 for both TOX and REL, the relative Q-TWiST gain was maintained (ranging from 11.0% to 21.2%; all significant) across varying utility values. Limitations include the sample size, the absence of utility estimates, and the length of adverse events from the trial. Conclusions: LEN + EVE showed a significant and clearly clinically important improvement in quality-adjusted survival time versus EVE alone. Patient summary: Patients with advanced kidney cancer who had received other previous treatments experienced a clearly clinically important improvement in quality survival time when treated with lenvatinib plus everolimus compared to everolimus alone.

Abstract Background In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy. Methods In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p

The clinical benefit from immunotherapy response in patients with mutations of genes forming the chromatin remodelling complex PBAF remains controversial. Here the authors show that PBAF complex mutations are not associated with favourable response in pan-cancer cohorts of patients treated with immune-checkpoint blockade.

Abstract Background Several phase 3 studies reported positive results for combinations of Immune-Oncology (IO) and Vascular Endothelial Growth Factor (VEGF) targeted therapies in patients with metastatic clear cell Renal Cell Carcinoma (ccRCC). However, there are limited data on outcomes to systemic therapy after IO-VEGF combinations. Methods A retrospective analysis was performed on patients with metastatic ccRCC treated at the Memorial Sloan Kettering Cancer Center and Cleveland Clinic who initiated systemic therapy post IO-VEGF including combinations with VEGF receptor (VEGFR) tyrosine kinase inhibitors (IO-TKI) and combinations with the anti-VEGF monoclonal antibody bevacizumab (IO-Bev). The study objectives were to evaluate the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) on systemic therapy post IO-VEGF. RECIST v1.1 criteria were used to determine radiological responses and progression. Survival estimates were evaluated with the Kaplan-Meier methods and the log-rank test from the start of systemic therapy post IO-VEGF to the event of interest. Results A total of fifty-nine patients were treated post discontinuation of IO-VEGF regimens which included IO-Bev (n = 35; 59%) and IO-TKI (n = 24; 41%). Fifty-eight patients (98%) received IO-VEGF regimens as part of a clinical trial. Subsequent therapies included cabozantinib (n = 22; 37%), axitinib (n = 18; 31%), pazopanib (n = 4; 7%), lenvatinib and everolimus (n = 4; 7%), mTOR inhibitor monotherapy (n = 3; 5%), axitinib and dalantercept (n = 2; 3%), sunitinib (n = 1; 2%), sorafenib (n = 1; 2%), and treatment with agents on unreported clinical trials (n = 4; 7%). Patients treated on unreported clinical trials were excluded from the efficacy analysis. Post IO-VEGF, the ORR was 25% and median PFS was 12.0 months (95% CI, 8.2–24.5). Median OS was 24.5 months (95% CI, 12–NE) and 12 months OS rate was 63.3% (95% CI, 48.6–74.9). We observed no differences post IO-VEGF OS when comparing IO- TKI vs IO-Bev (Log-rank p = 0.73). Conclusions Post IO-VEGF, most patients received VEGFR-TKIs. In this setting, VEGFR-TKIs demonstrated clinical activity and remain a viable option for salvage therapy after progression on IO-VEGF.

Background The phase 3 CheckMate 214 trial demonstrated higher response rates and improved overall survival with nivolumab plus ipilimumab versus sunitinib in first-line therapy for advanced clear-cell renal cell carcinoma (RCC). An unmet need exists to identify patients with RCC who are most likely to benefit from treatment with nivolumab plus ipilimumab.Methods In exploratory analyses, pretreatment levels of programmed death ligand 1 were assessed by immunohistochemistry. Genomic and transcriptomic biomarkers (including tumor mutational burden and gene expression signatures) were also investigated.Results Biomarkers previously associated with benefit from immune checkpoint inhibitor-containing regimens in RCC were not predictive for survival in patients with RCC treated with nivolumab plus ipilimumab. Analysis of gene expression identified an association between an inflammatory response and progression-free survival with nivolumab plus ipilimumab.Conclusions The exploratory analyses reveal relationships between molecular biomarkers and provide supportive data on how the inflammation status of the tumor microenvironment may be important for identifying predictive biomarkers of response and survival with combination immunotherapy in patients with RCC. Further validation may help to provide biomarker-driven precision treatment for patients with RCC.

Abstract The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Purpose To report updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC).Methods Patients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomised to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favourable-risk disease (FAV; exploratory).Results Overall, 1096 patients were randomised (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favourable with NIVO+IPI vs SUN.Conclusion After long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety.Trial registration details ClinicalTrials.gov identifier: NCT02231749.

Background The extent to which response and survival benefits with immunotherapy-based regimens persist informs optimal first-line treatment options. We provide long-term follow-up in patients with advanced renal cell carcinoma (aRCC) receiving first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the phase 3 CheckMate 214 trial. Survival, response, and safety outcomes with NIVO+IPI versus SUN were assessed after a minimum of 42 months of follow-up.Methods Patients with aRCC were enrolled from October 16, 2014, through February 23, 2016. Patients stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk and region were randomized to nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks; or SUN (50 mg) once per day for 4 weeks (6-week cycle). Primary endpoints: overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) per independent radiology review committee in IMDC intermediate-risk/poor-risk patients. Secondary endpoints: OS, PFS, and ORR in the intention-to-treat (ITT) population and safety. Favorable-risk patient outcomes were exploratory.Results Among ITT patients, 550 were randomized to NIVO+IPI (425 intermediate/poor risk; 125 favorable risk) and 546 to SUN (422 intermediate/poor risk; 124 favorable risk). Among intermediate-risk/poor-risk patients, OS (HR, 0.66; 95% CI, 0.55–0.80) and PFS (HR, 0.75; 95% CI, 0.62–0.90) benefits were observed, and ORR was higher (42.1% vs 26.3%) with NIVO+IPI versus SUN. In ITT patients, both OS benefits (HR, 0.72; 95% CI, 0.61–0.86) and higher ORR (39.1% vs 32.6%) were observed with NIVO+IPI versus SUN. In favorable-risk patients, HR for death was 1.19 (95% CI, 0.77–1.85) and ORR was 28.8% with NIVO+IPI versus 54.0% with SUN. Duration of response was longer (HR, 0.46–0.54), and more patients achieved complete response (10.1%–12.8% vs 1.4%–5.6%) with NIVO+IPI versus SUN regardless of risk group. The incidence of treatment-related adverse events was consistent with previous reports.Conclusions NIVO+IPI led to improved efficacy outcomes versus SUN in both intermediate-risk/poor-risk and ITT patients that were maintained through 42 months’ minimum follow-up. A complete response rate >10% was achieved with NIVO+IPI regardless of risk category, with no new safety signals detected in either arm. These results support NIVO+IPI as a first-line treatment option with the potential for durable response.Trial registration number NCT02231749.

Background Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown.Methods Genomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy.Results Del DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM. Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14–1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903).Conclusion Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.

Abstract Background RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients. Methods RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014. Results Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were

A subset of renal cell carcinomas have uncertain histology and are aggressive in nature. Here, the authors examine this group of unclassified renal cancers using genomics techniques and identify further subclasses of the tumours that have differing prognoses.